Congenital heart disease (CHD) is the most common human congenital malformation, occurring in 1-2% of all births. Classically, the genetics of non-syndromic CHD have been described as "multifactorial". However, there are well-established associations between CHD and specific single gene mutations, as well as numerous chromosome aberrations involving change in gene dosage. Evidence is accumulating that many developmental defects may be the result of genomic deletions of duplications invisible at the cytogenetic level and involving a small number of genes ("genomic disorders"). We hypothesize that the currently known microdeletion syndromes represent only a small proportion of the aberrations of this type, and that genomic disorders may be a significant cause of CHD. We will use ROMA, a newly developed microarray method capable of very high resolution (30kb) genome scanning for copy number changes (CNCs), to search for such lesions in 115 patients with hypoplastic left heart syndrome and 260 patients with conotruncal heart disease. After eliminating CNCs known to occur as normal variants, we will test parental DNAs to determine those arising de novo and confirm the lesions by FISH. Parental cardiac status will be assessed to elucidate causal familial changes with variable expression. Genes in the region will be prioritized as candidates for CHD by (1) the presence of recurrent lesions or lesions in chromosomal regions where aneuploidy leads to CHD (2) comparison with the set of genes known to be involved in CHD and (3) functional pathway analysis. Rates of genome anomalies will be compared among patients with different heart anomalies, those with and without other malformations, and those with and without growth retardation or cognitive delay. This study will determine the frequency with which genomic small CNCs lead to CHD, provide a new set of diagnostic tools for screening patients with CHD, and identify new candidate genes significant for heart development. [unreadable] [unreadable] Relevance: This study has the potential to identify new recurrent and non-recurrent genetic changes which are associated with congenital heart defects, the most common human birth defect. This would lead to new diagnostic tests that could be used both prenatally and postnatally, and could identify families at increased risk for congenital heart defects. In addition the study will serve as a prototype for future similar studies of small copy number changes associated with other developmental disorders and congenital malformations. [unreadable] [unreadable] [unreadable]